US8906414B1 - Methods and compositions for improving bioavailability of epigallocatechin gallate (EGCG) - Google Patents
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
Definitions
- This invention relates to catechins Specifically, the invention provides compositions and methods of improving the bioavailability of epigallocatechin gallate (EGCG).
- EGCG epigallocatechin gallate
- a ⁇ The ⁇ -amyloid peptide (A ⁇ ) is the major constituent of the neuritic plaques that together with the neurofibrillar tangles are physiologic hallmarks of Alzheimer's disease (AD).
- a ⁇ a 39-43 amino acid peptide, is derived from proteolytic cleavage of the amyloid precursor protein (APP), a type I integral membrane protein that is expressed ubiquitously.
- APP amyloid precursor protein
- APP can be processed via alternative pathways; a non-amyloidogenic secretory pathway includes cleavage of APP to soluble APP (sAPP) by a putative ⁇ secretase within the sequence of A ⁇ peptide, thus precluding the formation of A ⁇ , whereas the formation of the amyloidogenic A ⁇ peptides is regulated by the sequential action of ⁇ - and ⁇ -secretases. As the proportion of APP, processed by ⁇ -secretase vs. ⁇ -secretase, may affect the amount of A ⁇ produced, the regulation of these two pathways may be critically important to the pathogenesis of AD.
- sAPP soluble APP
- Proteolyic processing of APP can be regulated by activation of various cell-surface receptors coupled to increased activation of second messenger cascades, including phosphatidylinositol hydrolysis, tyrosine phosphorylation, protein kinase C (PKC), protein kinase A, mitogen-activated protein kinase, protein phosphatase 1 and 2B, and calcium.
- PKC protein kinase C
- mitogen-activated protein kinase protein phosphatase 1 and 2B
- calcium calcium
- a ⁇ toxicity and aggregation involve transition metals, oxidative stress, and accumulation of reactive oxygen species (ROS). It was also shown that A ⁇ neurotoxicity might be attenuated by numerous antioxidants and iron chelators. Recently, an increasing body of evidence points to a wide array of non-vitamin antioxidants, such as polyphenolic compounds, that can scavenge ROS, chelate transition metals, such as iron and copper and protect cells from oxidative damage. Indeed, ( ⁇ )-epigallocatechin-3-gallate (EGCG), the major polyphenol isolated from green tea, was shown in several studies to possess neuroprotective effects against a variety of toxic insults and neuronal injuries.
- EGCG ( ⁇ )-epigallocatechin-3-gallate
- Green tea contains polyphenolic structures categorized as flavonoids, which are believed to be the active components accounting for the therapeutic properties of green tea.
- EGCG ( ⁇ )-epigallocatechin-3-gallate
- EGCG has been found to modulate protein kinase C (PKC) activity and to consequently increase secreted levels of sAPP- ⁇ (Levites et al., 2002; Levites et al., 2003). Additionally, EGCG has been shown to inhibit various activities of proinflammatory cytokines (Ahmed et al., 2002; Han, 2003; Li et al., 2004). Accordingly, signal transducer and activator of transcription 1 and nuclear factor kB responses are inhibited by EGCG (Han, 2003; Aktas et al., 2004). Elucidation of these molecular actions of EGCG substantiates the compound as a versatile modulator of cellular responses that may contribute to disease pathogenesis.
- PLC protein kinase C
- EGCG treatment leads to a significant reduction in A ⁇ production as well as decreased A ⁇ levels and ⁇ -amyloid plaques in the brain. These effects are associated with increased generation of ⁇ -CTF and sAPP- ⁇ and elevated ⁇ -secretase cleavage activity, showing that EGCG promotes the nonamyloidogenic ⁇ -secretase proteolytic pathway both in vitro and in vivo.
- epigallocatechin gallate has recently gained the attention of scientists for implementation as a therapeutic agent for the treatment of many diseases.
- Current research suggests that EGCG has implications as a treatment for Alzheimer's disease and HIV-associated dementia (HAD).
- HAD HIV-associated dementia
- the full benefit of EGCG has yet to be fully realized due to its low bioavailability in vivo.
- an oral dose of 800 mg/70 kg/day provides approximately 400 ng/ml EGCG in human plasma.
- the inventors have recently shown that the dose of EGCG (1000-2000 ng/mL) is necessary for promoting APP ⁇ -secretase cleavage in SweAPP N2a cells.
- an oral dose of about 1800 mg/70 kg/day would be required. From a safety point of view, this dose might be unacceptable for clinical trials.
- EGCG amyloid precursor protein
- the composition is a nanoparticle complex comprised of a catechin, preferably EGCG, which is co-solubilized with a lipid carrier to form a nanoparticle complex that is preferably less than 80 nm in size and more preferably between 30 nm and 80 nm in size.
- the nanoparticle complex is preferably formed of 1 mg of lipid carrier and between about 8 mg and 16 mg of catechin.
- a further embodiment of the present invention is a method of increasing the bioavailability of a catechin, preferably EGCG, through the administration of a nanoparticle complex to treat a neurological disease such as Alzheimer's disease or HIV-associated dementia.
- compositions that is comprised of a catechin, preferably EGCG, encapsulated within a nanoparticle vesicle, preferably a liposome or niosome.
- the composition is preferably comprised of 1 mg of nanoparticle vesicle and between 8 mg and 16 mg of catechin.
- the composition is between 30 nm and 80 nm in size.
- a further embodiment of the present invention relates to a method of increasing the bioavailability of a catechin through the encapsulation of the catechin within the nanoparticle vesicle and administering the vesicle containing the catechin to a patient suffering from a neurological disease such as Alzheimer's disease or HIV-associated dementia.
- a further embodiment of the present invention includes a composition comprising a catechin, preferably EGCG and a solution of ethanol and water.
- a catechin preferably EGCG and a solution of ethanol and water.
- the composition is 90% EGCG and 10% ethanol and water solution.
- a further embodiment describes a method of increasing the bioavailability of a catechin, preferably EGCG, through the solubilization of the catechin in a solution of ethanol and water and administering it to a patient in need thereof.
- the patient in need thereof can be suffering from Alzheimer's disease and HIV-associated dementia (HAD), bacterial infection, virus infection, cancer, fatty liver disease, or hyperlipidemia.
- HAD Alzheimer's disease and HIV-associated dementia
- FIG. 1(A) is an ELISA immunoanalysis of EGCG/H 2 O versus EGCG/ethanol levels of soluble APP- ⁇ .
- (B) is a graph illustrating normalized sAPP- ⁇ concentration plotted against treatment concentration for EGCG/H 2 O versus EGCG/ethanol.
- FIG. 2 is a graph of the liposomal formulations against both water and an ethanol control.
- FIG. 3 is a graph of the mean pharmacokinetic curves for each liposome formulation tested and the control.
- FIG. 4 is a graph illustrating dynamic light scattering data.
- a Wyatt DynaPro Multiwell Reader was used to characterize the diameter of the NanoEGCG particles. The data indicates a narrow size distribution, with a cumulants mean of 49.5 nm and polydispersity of 0.052.
- FIG. 5 is a graph illustrating estimated sAPP- ⁇ generation for each treatment group.
- the sAPP- ⁇ concentration (ng/ml) was normalized to the total protein content (mg/ml). Data are presented as mean ng of sAPP- ⁇ per mg of total protein produced ⁇ standard deviation.
- the 1:8 and 1:16 formulations were superior to the other formulations, with the 1:8 showing 92% improvement in ⁇ -secretase activity over the EtOH control at the 3 ⁇ M concentration.
- the 1:8 NanoEGCG formulation was statistically higher than the control at all concentrations tested.
- the 1:16 NanoEGCG formulation was statistically higher at the lower two concentrations (***P ⁇ 0.001, **P ⁇ 0.01, *P ⁇ 0.05).
- the nanoparticle formulation resulted in substantial increase in systemic EGCG absorption.
- Statistical significance **P ⁇ 0.01 was observed at the 5 and 10 min time points.
- the 10% EtOH control had very poor absorption, with plasma concentration peaking at 116.57 ng/ml.
- the 1:16 NanoEGCG reached a maximum plasma concentration of 599.33 ng/ml.
- FIG. 7 is a table of the pharmacokinetic parameters comparing EGCG+10% EtOH, NanoEGCG (1:16), and NanoEGCG (1:8).
- Nanoparticle complex refers to a composition in which a drug complexes with, but not necessarily encapsulated within, a nanoparticle.
- the nanoparticle is preferably a lipid carrier.
- the drug becomes part of the nanoparticle as opposed to being encapsulated within the nanoparticle.
- a catechin such as EGCG is co-solubilized with a lipid carrier to produce nanoparticle complexes of a particular size, usually between 30 nm and 80 nm but any complex that is equal to or less than 80 nm can be used.
- Lipid carrier refers to a nanoparticle that is formed of lipids that is capable of forming a complex with a drug to enhance drug delivery.
- the lipid carrier can be formed from phospholipids particularly glycerophospholipids, or sterols such as cholesterol.
- Nanoparticle vesicle refers to small bubble-like vesicles that may be used as a drug-delivery system.
- the vesicles may be comprised of lipids such as phospholipids, cholesterol and non-ionic surfactants, copolymers, biodegradable and biocompatible polymers such as chitosin, PLA, PLGA, and starch.
- Drugs may be encapsulated within the nanoparticle vesicle to enhance bioavailability of the drug.
- Nanoparticle vesicles include, but are not limited to, liposomes, niosomes, micelles, multilamellar vesicles, unilamellar vesicles, and polymersomes.
- the nanoparticle vesicles can be between 1 nm and 250 nm (generally over 100 nm) and can encapsulate the drug to be delivered. These vesicles self-assemble during preparation. While the nanoparticle vesicles can range in size, those used in the present invention are preferably between 30 nm and 80 nm so as to be able to pass the blood-brain barrier.
- Neurological disease refers to diseases or impairments of the neurological system.
- the terms “neurological disease” include but are not limited to diseases such as Alzheimer's disease and HIV-associated dementia (HAD) as well as other dementias.
- HAD HIV-associated dementia
- “Patient” is used to describe an animal, preferably a human, to whom treatment is administered, including prophylactic treatment with the compositions of the present invention.
- a therapeutically effective amount of the compositions of the present invention is that amount necessary to provide a therapeutically effective result in vivo.
- the amount of composition must be effective to achieve a response, including but not limited to total prevention of (e.g., protection against) and to improved survival rate or more rapid recovery, or improvement or elimination of symptoms associated with neurological diseases such as Alzheimer's disease and HIV-associated dementia (HAD), bacterial infection, virus infection, cancer, fatty liver disease, hyperlipidemia or other indicators as are selected as appropriate measures by those skilled in the art.
- HAD Alzheimer's disease and HIV-associated dementia
- a suitable single dose size is a dose that is capable of preventing or alleviating (reducing or eliminating) a symptom in a patient when administered one or more times over a suitable time period.
- One of skill in the art can readily determine appropriate single dose sizes for systemic administration based on the size of a mammal and the route of administration.
- administering is used to describe the process in which the compositions of the present invention are delivered to a patient.
- the composition may be administered in various ways including oral as well as parenteral (referring to intravenous and intraarterial and other appropriate parenteral routes) among others.
- Dosages for the nanoparticle vesicle compositions as well as the nanoparticle complexes preferably consist of a ratio of 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, and 1:16 with the ratio being 1 mg of nanoparticle vesicle or lipid carrier and between 8 mg and 16 mg of catechin.
- AD Alzheimer's disease
- HAD HIV-associated dementia
- Alzheimer's disease AD
- VaD vascular dementia
- HID human immunodeficiency virus type 1 associated dementia
- EGCG Epigallocatechin gallate
- Epigallocatechin gallate has been implicated as a potential target for nutraceutical development due to its antioxidant activity, chemopreventative activity, and its ability to prevent obesity.
- the integration of EGCG into existing products has been slow, some of which can probably be attributed to the high concentration that is required to achieve therapeutic action (because of the low bioavailability in vivo), which consequently increases the cost of production unnecessarily (since most of the EGCG is eliminated from the body).
- HDL high-density lipoprotein
- EGCG EGCG suspended in an ethanol plus water solution enhances the action of EGCG.
- Plasma concentrations were measured in rats that were dosed orally with 90% pure EGCG in a 10% ethanol (EtOH) plus water (H 2 O) solution.
- EtOH 10% ethanol
- H 2 O water
- FIG. 1 significant increases in the bioavailability of EGCG occurred when it is delivered in the EtOH vehicle compared to H 2 O and EGCG alone.
- EtOH was tested for its ability to promote alpha secretase activity in vitro, using N2A cells that were transfected with the Swedish mutant of APP (swAPP), a common model for Alzheimer's disease. It was found that the EGCG in EtOH showed increased ⁇ -secretase activity.
- EGCG can be used not only as a therapeutic for life-threatening diseases, like Alzheimer's, but that it can also be used as a general health supplement, combating age-related oxidative damage, promoting weight loss, preventing the onset of fatty liver disease, and more.
- alcoholic beverages can be the best-suited vehicle for EGCG.
- alcohol consumption in moderation is can lead to longer life and fewer instances of heart disease.
- One negative effect of alcohol abuse is fatty liver disease, the accumulation of excess triglycerides inside the liver cells.
- EGCG can be useful as a therapeutic treatment for people with fatty liver disease.
- Both EGCG and EtOH alone have been found independently to improve lipid profiles by reducing LDL and increasing HDL cholesterol blood levels in both animal and human studies.
- the combination of EGCG and EtOH can be administered to a patient to treat hyperlipidemia based on the enhanced therapeutic action on lipid profiles.
- Antioxidants have gained the attention of researchers around the world, both in industry and academia. These compounds are required by the body to scavenge free radicals that would otherwise cause damage at the cellular level. Oxidative stress (caused by an imbalance between oxidants and antioxidants) has been identified as the major cause in many neurodegenerative diseases, cancer, and other age-related diseases. Although humans produce intrinsic enzymatic antioxidants like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase, the ability to prevent oxidative damage relies heavily on antioxidants obtained from dietary sources. EGCG is a non-enzymatic antioxidant having the ability to modulate neuroinflammation in Alzheimer's disease (AD) pathology and HIV-associated dementia (HAD).
- AD Alzheimer's disease
- HAD HIV-associated dementia
- FIG. 2 shows a compilation of all of the liposome formulations against both a water and ethanol control.
- the cell culture assays are well within the water solubility limitations of EGCG.
- the liposomes were prepared for in vivo testing and were much more concentrated in the stock solution. Ethanol was used to solubilize the EGCG and as an important step during the encapsulation process.
- FIG. 3 shows a compilation of the mean pharmacokinetic curves for each liposome formulation tested and the control. Because EGCG is poorly water soluble, 10% EtOH was added to fully solubilize the EGCG and ensure accurate dosing in the control. The data shows that the liposome formulations result in drastic increases in absorption of EGCG.
- Green tea-derived EGCG (>95% purity by HPLC), was purchased from Sigma Chemical Co. (St Louis, Mo., USA). BCA protein assay kit was purchased from Pierce Biotechnology (Rockford, Ill., USA). Anti-human amyloid- ⁇ antibodies 4G8 and 6E10 were obtained from Signet Laboratories (Dedham, Mass., USA) and Biosource International (Camarillo, Calif., USA), respectively.
- Liposome preparation was performed as shown in Fountain et al. U.S. patent application Ser. No. 11/644,281, herein incorporated in its entirety by reference.
- mice Male Sprague Dawley rats weighing 200-250 g were purchased from Harlan Laboratories (Indianapolis, Ind.). The rats were purchased pre-cannulated by Harlan. The cannulas had a round tip that was surgically implanted into the jugular vein of the rats making multiple blood draws painless to the animal. The rats were food, but not water, deprived for 18 hours prior to the start of the experiment. The EGCG formulations were delivered via oral gavage at a dosage of 100 mg/kg. Blood was drawn at the following time points: 0, 5, 10, 30, 60, 120, 240, 480, 600, 2880 minutes.
- heparin was kept in the catheter lines to prevent clotting, some blood was drawn and discarded before collecting each sample. Approximately 300 ⁇ L of blood was collected in EDTA tubes for each time point. The samples were kept on ice to preserve their integrity then centrifuged at 4000 rpm for 10 minutes, afterwhich the plasma was transferred to sterile centrifuge tubes. A preservative solution was added to each plasma sample at 10% (v/v) concentration to ensure the integrity of the EGCG during storage. This preservative was comprised of 20% ascorbic acid (to prevent oxidation of EGCG) and 0.1% EDTA (to scavenge any metal contaminants). The samples were stored at ⁇ 80° C. until they were analyzed for EGCG content.
- the plasma samples were blinded and sent to be analyzed for EGCG content by the Burnham Institute for Medical Research Pharmacology Core (Orlando, Fla.). To most accurately quantify the concentration of EGCG in the plasma, a previously described method was employed using liquid chromatography with tandem mass spectrometry.
- Nanoparticles and larger liposomes have been investigated extensively for increasing the oral bioavailability of poorly absorbed compounds (Frezard et al., 2008; He et al., 2007; Kumar et al., 2007; Pandey et al., 2005; Rao et al., 2008). It has been recently reported that encapsulating EGCG into liposomes can improve its anti-cancer efficacy (Siddiqui et al., 2009) and antioxidant capacity (Italia et al., 2008). However, these studies utilized larger diameter particles (>100 nm) and focused primarily on improved efficacy of EGCG for specific disease modifying parameters.
- NanoEGCG Nanolipidic particle formation
- These nanoparticles differ from traditional liposomes because they do not require micelle formation. Rather, they are drug:lipid complexes. This enables the formation of smaller diameter particles that are useful for increasing the oral bioavailability of EGCG.
- an oral dose of 800 mg/70 kg/day provides approximately 400 ng/ml EGCG in human plasma (Chow et al., 2001). Given that the inventors have recently shown that 1000-2000 ng/mL of free EGCG is necessary for promoting APP ⁇ -secretase cleavage in SweAPP N2a cells (Rezai-Zadeh et al., 2005), using linear approximation, an oral dose of EGCG of 1800 mg/70 kg/day would be required to reach therapeutically effective plasma concentrations of EGCG. From a safety and practicality point of view, this dose might be unacceptable for clinical trials (Ullmann et al., 2004, 2003).
- EGCG nanolipidic complexes it is possible to increase the oral bioavailability of EGCG as well as its AD and HAD preventative and therapeutic actions, without affecting the absorption of other ingested compounds. This is an important factor to consider when bringing an EGCG therapeutic into the clinical setting.
- the inventors modified EGCG such that it requires no co-administration of other drugs. Rather, it is co-solubilized with a lipid carrier using proprietary methodology to form 30-80 nm diameter nanoparticle complexes.
- the importance of particle diameter for drug delivery is particularly important for delivery of drugs to the brain (Wissing et al., 2004).
- Previously, even smaller diameter liposomes (100 nm) have had trouble penetrating the tight junctions between the endothelial cells of the blood brain barrier without osmotic disruption (Sakamoto and Ido, 1993). This highlights an important distinction between this nanoparticle technology and previous liposomal technologies, which require micelle formation.
- NanoEGCG does not involve encapsulating the EGCG into a micelle.
- lipid:EGCG complexes are formed. Because the EGCG is not fully encased in a micelle structure, it is possible to achieve smaller diameter particles without compromising the stability of the carrier. While the inventors have demonstrated the ability of nanoparticles to increase the systemic absorption of EGCG taken orally, the small diameter of these particles leads to improved blood brain barrier penetration.
- Nanolipidic particles are useful for safely translating EGCG into human clinical trials. Not only did NanoEGCG more than double the oral bioavailability of EGCG in rats ( FIG. 6 ) but also was more effective at promoting ⁇ -secretase activity in vitro, even at reduced concentrations ( FIG. 7 ). Taken together, NanoEGCG is therapeutically effective at doses that would be considered acceptable in the clinical setting.
- Green tea-derived EGCG (>95% purity by HPLC) was used for the experiments.
- the BCA protein assay kit was purchased from Pierce Biotechnology (Rockford, Ill., USA).
- Antihuman amyloid- ⁇ antibodies 4G8 and 6E10 were obtained from Signet Laboratories (Dedham, Mass., USA) and Biosource International (Camarillo, Calif., USA), respectively.
- Nanolipidic EGCG Particles (NanoEGCG)
- Nanolipidic particles were prepared using a proprietary co-solubilization methodology involving use of monophasic liquid preparations developed by Nature's Defense Systems, Tampa, Fla. The particles were prepared according to the methods described in U.S. patent Ser. No. 11/644,281 to Fountain, herein incorporated in its entirety by reference. As described in Fountain, in preparing the monophasic liquid preparations, a precursor solution is made by solubilizing an amphipathic material in a first quantity of a non-aqueous solvent appropriate to solubilize the amphipathic material to form a first mixture.
- the amphipathic material may comprise phospholipids (PL) in a mixture of the following phosphatides: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA) and phosphatidylinositol (PI) at a ratio of PC:PE:PA:PI of 6.5:2.5:0.7:0.3 in ethanol.
- PC phosphatidylcholine
- PE phosphatidylethanolamine
- PA phosphatidic acid
- PI phosphatidylinositol
- one gram of PL is solubilized in 5.0-7.5 ml of ethanol solvent.
- a quantity of water is added to form a turbid suspension.
- the amount of water to add is approximately 9 kg to 31 kg of dissolved amphipathic material, but can be varied to result in the desired turbid suspension.
- NanoEGCG co-solubilization methodology involving use of monophasic liquid preparations were employed with proprietary starting materials. These materials are first solubilized into a water-in-ethanol solution (step 1).
- NanoEGCG particles were formed by the addition of distilled water while mixing materials (step 3). The final preparation of NanoEGCG particles was stirred for an additional 10 min prior to subjecting the preparation to sizing analysis with a Wyatt DynaPro Multiwell Reader (Wyatt Technology Corporation, Santa Barbara, Calif.).
- FIG. 4 shows a representative analysis of the size distribution of the 1:8 NanoEGCG formulation.
- the stock formulations were stored at 20° C. and protected from light until needed.
- sAPP- ⁇ levels were quantified using a sAPP- ⁇ sandwich ELISA protocol as previously described (Bailey et al., 2008).
- High binding 96-well plates (Nunc, Denmark) were coated with monoclonal antibody 22C11 diluted in 100 ⁇ L (1 ⁇ g/mL) of carbonate buffer (pH 9.6) and incubated overnight at 4° C.
- the plate was washed five times with PBS-Tween buffer (0.05% Tween 20) and blocked with 300 ⁇ L of blocking buffer (1% BSA and 5% Horse Serum in PBS) for 2 h at 37° C.
- Synthetic sAPP- ⁇ protein (Abgent, San Diego, Calif.) was used as the positive control for this ELISA.
- mice Male Sprague Dawley rats weighing 200-250 g were purchased from Harlan Laboratories (Indianapolis, Ind.). The rats were precannulated by Harlan. The rounded tip catheters were surgically implanted into the jugular vein of the rats making multiple, precise blood draws painless to the animal. The rats were food (not water) deprived for 18 h prior to the start of the experiment. The EGCG formulations were delivered via oral gavage at a dosage of 100 mg EGCG/kg body weight. Blood was collected at the following time points: 0, 5, 10, 30, 60, 120, 240, and 480 min. Because heparin was kept in the catheter lines to prevent clotting, a small amount of blood was drawn and discarded before collecting each sample.
- the plasma samples were blinded and sent to be analyzed for EGCG content by the Burnham Institute for Medical Research Pharmacology Core (Orlando, Fla.).
- Burnham Institute for Medical Research Pharmacology Core (Orlando, Fla.).
- a previously described method was employed using liquid chromatography with tandem mass spectrometry (Sparidans et al., 2007; Wang and Miksa, 2007; Wang et al., 2004, 2000).
- FIG. 5 shows the mean ng of sAPP- ⁇ per mg of total protein produced ⁇ standard deviation for all EGCG formulations.
- NanoEGCG formulations were effective. In fact, the 1:1 and 1:2 formulations were outperformed by the EGCG and 10% Et0H/H2O control at all concentrations tested.
- the 1:8 and 1:16 NanoEGCG formulations were selected to be advanced to the pharmacokinetics phase of the study because they outperformed the control at all concentrations tested.
- the 1:8 formulation was statistically significant at all concentrations, whereas the 1:16 was only statistically significant at the lower two concentrations. Not only did these formulations show marked increases in sAPP- ⁇ generation but, perhaps more importantly, they continued to promote enhanced levels of ⁇ -secretase activity even at the lowest EGCG concentration tested.
- FIG. 6 shows a compilation of the mean pharmacokinetic curves for the nanoparticle formulation tested and the control. Because EGCG is poorly water soluble, 10% EtOH was added to fully solubilize the EGCG at a concentration equivalent to the NanoEGCG stock (50 mg/ml) and ensure accurate dosing in the control. The data shows that the nanoparticle formulations result in substantial increases in the absorption of EGCG. Although FIG. 6 indicates only one NanoEGCG curve, both 1:8 and 1:16 formulations were tested. However, both nanoparticle formulations were similarly absorbed and not statistically different, so the 1:16 preparation was selected to represent the NanoEGCG pharmacokinetic curve.
- FIG. 7 shows some important pharmacokinetic parameters: Cmax, Tmax, AUC, and relative bioavailiblity.
- the relative bioavailability (defined by the AUC) of the NanoEGCG was 2.31 and 2.50 for the 1:16 and 1:8 formulations, respectively, in comparison to the free EGCG in 10% EtOH solution (10% EtOH control).
Abstract
Description
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WO2021242545A1 (en) * | 2020-05-29 | 2021-12-02 | The Regents Of The University Of California | Agents and methods for treating tauopathies |
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